Breast Milk Sugar Plus Bifidobacteria Reshapes Infant Gut and Prevents Eczema in Mice

Atopic dermatitis (AD), the most common inflammatory skin condition in infancy, is strongly associated with gut microbiota dysbiosis characterized by depleted Bifidobacterium species and elevated pathogenic bacteria such as Klebsiella and Escherichia coli. Human milk oligosaccharides, particularly 2'-fucosyllactose (2'-FL), are known to support healthy microbial colonization, but infants with AD harbor gut communities with impaired capacity to ferment 2'-FL into protective short-chain fatty acids (SCFAs). This study asked whether supplementing with cross-feeding bifidobacteria alongside 2'-FL could correct this metabolic deficit and, if so, whether the restored microbiota could prevent AD.

The team first characterized two strains isolated from human milk in a low-AD-prevalence county in China: B. bifidum FN120 (an extracellular HMO degrader) and B. longum subsp. longum FN103 (a cross-feeder consuming degradation products including fucose and lactose). In single vs. co-culture experiments with 1% 2'-FL as the sole carbon source, co-culture at 1:1 ratio reached significantly higher OD600 growth readings than either strain alone, confirming functional cross-feeding synergy. Genome sequences of both strains were deposited under BioProject IDs PRJNA1218428 and PRJNA1218424.

Fecal samples from six exclusively breastfed male infants with AD (mean age ~37 days, no prior antibiotic or probiotic exposure) were inoculated into individual bioreactors in a multifunctional gastrointestinal fermentation simulator. Continuous fermentation ran through three stages: a 10-day lactose stabilization period (STAB), a 7-day 2'-FL intervention (replacing lactose with 1% 2'-FL), and a 7-day combined intervention adding 1×10⁹ CFU/day of FN120+FN103 (2'-FL+Bif). SCFA analysis showed that acetate and propionate concentrations rose significantly across the three stages, with the combined 2'-FL+Bif stage producing the greatest SCFA increases. 16S rRNA microbiota profiling demonstrated a progressive reshaping of the dysbiotic community, with Bifidobacterium abundance rising markedly and pathobiont taxa declining under the combined intervention.

To test in vivo relevance, fermentation broths from donor 2 at each stage were transplanted into antibiotic-pre-treated male BALB/c mice (n=8/group, 6 groups total) before oxazolone (OXA) challenge. Mice receiving the 2'-FL+Bif-stage microbiota showed the most robust prevention of AD: skin inflammation scores, histological damage, and IgE-related markers were significantly lower compared to STAB_OXA and Healthy_OXA groups. Ileum microbiota composition mirrored the ex vivo changes, and intestinal SCFA levels were elevated. RNA sequencing of Peyer's patches — critical gut-associated lymphoid tissue — revealed that the retinol metabolic pathway was the top activated pathway in the 2'-FL+Bif-transplanted mice. Nontargeted plasma metabolomics confirmed a significant increase in retinoate (an active vitamin A metabolite) levels that correlated strongly with reductions in key AD biomarkers, suggesting that retinoic acid-driven immune tolerance was a core protective mechanism.

Collectively, the study constructs a mechanistic chain: 2'-FL + cross-feeding bifidobacteria → SCFA production + microbiota normalization → retinol metabolic pathway activation in Peyer's patches → elevated plasma retinoate → immune tolerance → prevented AD. The findings highlight the gut–skin axis and suggest that the failure of 2'-FL alone to protect AD-prone infants can be overcome by co-supplementing with strains capable of initiating cross-feeding cascades. Limitations include use of only male infant donors (to control for sex-based microbiota variability), a small cohort of six AD donors, a single healthy infant control, and the translational gap between mouse OXA models and human infantile AD.